Bulik, Melissa
(2024)
Transcriptional dysregulation associated with pathologic development and maintenance of myofibroblasts in systemic sclerosis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Systemic sclerosis (SSc) is rare disease that is both complex and heterogenous. It can affect multiple organ systems and varies greatly in severity. The leading cause of SSc-related mortality is lung fibrosis, i.e., interstitial lung disease (ILD). Patients with SSc-ILD have an expanded population of myofibroblasts in their lungs. Myofibroblasts contribute to pathogenicity through their ability to increase extracellular matrix and the formation of fibrotic foci. In end-stage lung disease, there is a major distortion of the pulmonary architecture and diminished gas exchange. The transcriptional drivers of myofibroblasts are incompletely understood, particularly in the direct context of the human disease. My research has focused on two areas of dysregulation.
In the first, I used single cell data collected from control and SSc-ILD lungs, to identify upregulated expression of transcription factor 12 (TCF12), along with downstream target genes, within the myofibroblast population using pySCENIC. Perturbation of TCF12 in vitro identified altered gene expression implicating pathways associated with actin regulation, TGF- signaling, and cell cycle interruption. Overexpression of TCF12 led to upregulation of SSc associated genes. TCF12 overexpression was also associated with differentially accessible regions in chromatin compared to baseline TCF12 expression. These data support the role of aberrant TCF12 activity in SSc-ILD myofibroblasts.
My second focus was to associate skewing of chromatin accessibility and transcription factor binding site access with single nucleotide variants (SNVs) that have been associated by GWAS with SSc. I found that nearly 20% of the investigated SNVs were enriched for SMAD2 binding motifs, noteworthy because of the role TGF- is thought to play in SSc. Though none of the SMAD2 sites are altered by the index SNV, these data suggest that these loci are important in pathogenesis. Determining dysregulation in gene expression of the myofibroblast can provide insight into the disease progression and potentially allow for the development of new therapeutics. These projects have helped define the roles of TGF- and TCF12 in myofibroblast differentiation and may provide insight into treatment plans for SSc-ILD patients.
Public Health Significance: Pulmonary fibrosis is a life-threatening disease. Understanding the regulation of myofibroblasts can aid the development of new treatment options.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 January 2024 |
| Defense Date: |
24 October 2023 |
| Approval Date: |
4 January 2024 |
| Submission Date: |
3 January 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
135 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Transcription factor 12, TCF12, HEB, Myofibroblast regulation, Systemic sclerosis, Interstitial lung disease, Pulmonary fibrosis, Regulon activity, Transcription factor binding site, Chromatin accessibility |
| Date Deposited: |
04 Jan 2024 18:05 |
| Last Modified: |
04 Jan 2024 18:05 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45749 |
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